Acquired immunodeficiency syndrome (referred to as “AIDS” hereinafter) is the disease caused by the infection of HIV. The investigations for medicaments to treat this disease have been actively performed, and although medicaments such as azidothymidine (referred to as “AZT” hereinafter) and dideoxyinosine (referred to as “DDI” hereinafter) have been practically used, they have some problems in their effects or side effects. Thus, medicaments which can completely treat the diseases caused by HIV infection have not been found and there is no prospect of the findings. On the other hand, a vaccine as a tool for preventing HIV infection and suppressing AIDS onset, which enhances the immune resistance against HIV, has been expected as a critical key to control the global and rapid spread of the disease and has been widely investigated. To date, various types of vaccine have been investigated and some of them are undergoing the clinical test.
The vaccines which have been reported to date include:
i) Vaccines which utilizes inactivated or attenuated virus particles: The method may be considered wherein a gene responsible for HIV pathogenicity is mutated or deleted (Proc. Natl. Acad. Sci. USA, 84, 1434, 1987) or the approach wherein related viruses such as simian viruses which shares the antigenecity of HIV are used (Science, 232, 238, 1987), but it would be difficult to practically use them due to their potential risks.
ii) Subunit vaccines utilizing partial antigen proteins from the viral antigenic proteins: This is the approach wherein only a partial antigenic protein of the virus particle is produce, for example, by genetic recombinant procedures and used as an immunogen (Proc. Natl. Acad. Sci. USA, 84, 6924, (1987), Ann. Int. Med., 114, 119, (1991), Nature, 355, 728, 1992). This approach is widely attempted and there are many clinical test cases. However, there are many problems such as poor increase in the titer of the neutralizing antibody or the persistency of the titer of the antibody. Also, although it would be expected for this approach that it would be effective in enhancing the humoral immunity such as the production of antibodies, the effect of this approach alone would not be necessary expected considering the infection manner of HIV, because this approach would not lead to the activation of cellular immunity which can kill the infected cells.
iii) Recombinant live vaccines such as vaccinia virus or BCG: This is the approach wherein a partial gene sequence from HIV is introduced into the gene of vaccinia virus (Nature, 332, 728, 1988) or BCG (Nature, 351, 479, 1991) which can propagate in human cells. Theoretically, the enhancing effect on cellular immunity would be expected but there are some problems, for example, in that at least previously produced recombinant live vaccines of vaccinia did not trigger sufficient immune response, or viruses such as vaccinia, which are usually harmless, have the possibility of severe infection (Lancet et al. 337, 1034, 1991).
iv) Anti-idiotype antibodies: This is the approach wherein an anti-idiotype antibody is used as the alternative to the virus antigen (Proc. Natl. Acad. Sci. USA, 89, 2546, 1992).
v) Synthetic peptide vaccines: Synthesized peptides are considered in this approach, wherein the sequences of the determinant region of neutralizing antibodies are chemically synthesized.
The above described vaccines are of the type of humoral immune enhancer which mainly induce the neutralizing antibodies, while it is believed that cytotoxic T cells (referred to as “CTLs” hereinafter) which can impair infected cells are more important in defending the infection than humoral immunity with neutralizing antibodies, considering that HIV spreads more easily through the cell fusion between infected cells and non-infected cells than through virus particles. Actually, there is a report where if the patients who had been exposed to the chance of HIV infection were investigated, HIV specific CTLs were detected (J. Clin. Invest., 93, 1293, (1994), Nature, Med., 1, 59, 1995). There is also a report wherein HIV carrying a mutated CTL epitope can escape from the attack of CTLs (Nature Med., 3, 205, 1997) and the appearance of HIV carrying such mutated epitope is believed to be the cause of the onset of AIDS in patients chronically infected with HIV (Nature Med., 3, 212, 1997).
Antigens such as virus-derived proteins are endogenously processed in cells to short fragments and are presented on the cell surface as a bounded form with major histocompatibility complex (referred to as “MHC” hereinafter). CTL recognizes the epitope peptide presented by Class I MHC antigen expressed on the cell surface and attack the target cells. More specifically, CTL recognizes both of the processed antigen fragment bound to the groove of MHC molecule and a part of the MHC molecule on the target cell simultaneously and attack the cell carrying them. Thus, the antigen recognition of CTL intensively depends on MHC on the cell surface. Such antigen recognition is called MHC restriction. It is known that the epitope peptides which bind to a particular MHC Class I antigen and which are presented by the antigen have about nine amino acids in length and their amino acids sequences are defined by certain rules (motif) (Nature, 351, 290, 1991, Eur. J. Immunol., 22, 2453, 1992, Nature, 353, 326, 1991, Nature, 360, 434, 1992, Immunogenetics, 38, 161, 1993).
Based on these findings, the inventors of the present invention have been searching CTL peptides which specifically impair HIV-1 infected cells and have already defined the peptides which can bind to HLA-B35, HLA-B51 and HLA-A31 among human Class I antigens, human Class I leukocyte antigens (referred to as “HLA” hereinafter), and which can induce HIV-1 specific CTLs (WO 95/11255). These peptides induced HIV-1 specific CTLs, restricted by each HLA alloantigen type.
Since HLA genes are the genes having very high diversities, the peptides which bind to HLA Class I antigens have also high diversities, although they comply with certain rules. This suggests that the peptides which are effective in the prevention and/or treatment of HIV infection may possibly differ among individuals, ethnic populations and the like. Therefore, in the prevention and/or the treatment of HIV infection wherein such peptides are used, a set of peptides is desired which can induce other HLA-restricted CTLs besides the known peptide groups.